Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer
Background Inflammatory mammary cancer (IMC), the counterpart of human inflammatory breast cancer (IBC), is the deadliest form of canine mammary tumors. IMC patients lack specific therapy and have poor outcomes. This proof-of-principle preclinical study evaluated the efficacy, safety, and effect on...
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004044.full |
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| author | Daniel Alonso-Miguel Guillermo Valdivia Diego Guerrera Maria Dolores Perez-Alenza Stanislav Pantelyushin Angela Alonso-Diez Veronique Beiss Steven Fiering Nicole F Steinmetz Maria Suarez-Redondo Johannes vom Berg Laura Peña Hugo Arias-Pulido |
| author_facet | Daniel Alonso-Miguel Guillermo Valdivia Diego Guerrera Maria Dolores Perez-Alenza Stanislav Pantelyushin Angela Alonso-Diez Veronique Beiss Steven Fiering Nicole F Steinmetz Maria Suarez-Redondo Johannes vom Berg Laura Peña Hugo Arias-Pulido |
| author_sort | Daniel Alonso-Miguel |
| collection | DOAJ |
| description | Background Inflammatory mammary cancer (IMC), the counterpart of human inflammatory breast cancer (IBC), is the deadliest form of canine mammary tumors. IMC patients lack specific therapy and have poor outcomes. This proof-of-principle preclinical study evaluated the efficacy, safety, and effect on survival of neoadjuvant intratumoral (in situ) empty cowpea mosaic virus (eCPMV) immunotherapy in companion dogs diagnosed with IMC.Methods Ten IMC-bearing dogs were enrolled in the study. Five dogs received medical therapy, and five received weekly neoadjuvant in situ eCPMV immunotherapy (0.2–0.4 mg per injection) and medical therapy after the second eCPMV injection. Efficacy was evaluated by reduction of tumor growth; safety by hematological and biochemistry changes in blood and plasma; and patient outcome by survival analysis. eCPMV-induced immune changes in blood cells were analyzed by flow cytometry; changes in the tumor microenvironment were evaluated by CD3 (T lymphocytes), CD20 (B lymphocytes), FoxP3 (Treg lymphocytes), myeloperoxidase (MPO; neutrophils), Ki-67 (proliferation index, PI; tumor cell proliferation), and Cleaved Caspase-3 (CC-3; apoptosis) immunohistochemistry.Results Two neoadjuvant in situ eCPMV injections resulted in tumor shrinkage in all patients by day 14 without systemic adverse events. Although surgery for IMC is generally not an option, reduction in tumor size allowed surgery in two IMC patients. In peripheral blood, in situ eCPMV immunotherapy was associated with a significant decrease of Treg+/CD8+ ratio and changes in CD8+Granzyme B+ T cells, which behave as a lagging predictive biomarker. In the TME, higher neutrophilic infiltration and MPO expression, lower tumor Ki-67 PI, increase in CD3+ lymphocytes, decrease in FoxP3+/CD3+ ratio (p<0.04 for all comparisons), and no changes in CC-3+ immunostainings were observed in post-treatment tumor tissues when compared with pretreatment tumor samples. eCPMV-treated IMC patients had a statistically significant (p=0.033) improved overall survival than patients treated with medical therapy.Conclusions Neoadjuvant in situ eCPMV immunotherapy demonstrated anti-tumor efficacy and improved survival in IMC patients without systemic adverse effects. eCPMV-induced changes in immune cells point to neutrophils as a driver of immune response. Neoadjuvant in situ eCPMV immunotherapy could be a groundbreaking immunotherapy for canine IMC and a potential future immunotherapy for human IBC patients. |
| format | Article |
| id | doaj-art-c925ae8c4b2e44539ed0f0f302b29ca8 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-c925ae8c4b2e44539ed0f0f302b29ca82025-08-20T03:08:17ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-004044Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancerDaniel Alonso-Miguel0Guillermo Valdivia1Diego Guerrera2Maria Dolores Perez-Alenza3Stanislav Pantelyushin4Angela Alonso-Diez5Veronique Beiss6Steven Fiering7Nicole F Steinmetz8Maria Suarez-Redondo9Johannes vom Berg10Laura Peña11Hugo Arias-Pulido12Department of Animal Medicine, Surgery and Pathology, Mammary Oncology Unit, Veterinary Teaching Hospital, Veterinary Medicine School, Complutense University of Madrid, Madrid, SpainDepartment of Animal Medicine, Surgery and Pathology, Mammary Oncology Unit, Veterinary Teaching Hospital, Veterinary Medicine School, Complutense University of Madrid, Madrid, SpainInstitute of Laboratory Animal Science, University of Zurich, Schlieren, SwitzerlandDepartment of Animal Medicine, Surgery and Pathology, Mammary Oncology Unit, Veterinary Teaching Hospital, Veterinary Medicine School, Complutense University of Madrid, Madrid, SpainInstitute of Laboratory Animal Science, University of Zurich, Schlieren, SwitzerlandDepartment of Animal Medicine, Surgery and Pathology, Mammary Oncology Unit, Veterinary Teaching Hospital, Veterinary Medicine School, Complutense University of Madrid, Madrid, SpainBioengineering, University of California San Diego, La Jolla, California, USA4Geisel School of Medicine at Dartmouth, Lebanon, NH, USA6Nanotechnology Characterization Laboratory, Frederick, MD, USADepartment of Animal Medicine, Surgery and Pathology, Mammary Oncology Unit, Veterinary Teaching Hospital, Veterinary Medicine School, Complutense University of Madrid, Madrid, SpainInstitute of Laboratory Animal Science, University of Zurich, Schlieren, SwitzerlandDepartment of Animal Medicine, Surgery and Pathology, Mammary Oncology Unit, Veterinary Teaching Hospital, Veterinary Medicine School, Complutense University of Madrid, Madrid, SpainDartmouth Geisel School of Medicine, Lebanon, NH, USABackground Inflammatory mammary cancer (IMC), the counterpart of human inflammatory breast cancer (IBC), is the deadliest form of canine mammary tumors. IMC patients lack specific therapy and have poor outcomes. This proof-of-principle preclinical study evaluated the efficacy, safety, and effect on survival of neoadjuvant intratumoral (in situ) empty cowpea mosaic virus (eCPMV) immunotherapy in companion dogs diagnosed with IMC.Methods Ten IMC-bearing dogs were enrolled in the study. Five dogs received medical therapy, and five received weekly neoadjuvant in situ eCPMV immunotherapy (0.2–0.4 mg per injection) and medical therapy after the second eCPMV injection. Efficacy was evaluated by reduction of tumor growth; safety by hematological and biochemistry changes in blood and plasma; and patient outcome by survival analysis. eCPMV-induced immune changes in blood cells were analyzed by flow cytometry; changes in the tumor microenvironment were evaluated by CD3 (T lymphocytes), CD20 (B lymphocytes), FoxP3 (Treg lymphocytes), myeloperoxidase (MPO; neutrophils), Ki-67 (proliferation index, PI; tumor cell proliferation), and Cleaved Caspase-3 (CC-3; apoptosis) immunohistochemistry.Results Two neoadjuvant in situ eCPMV injections resulted in tumor shrinkage in all patients by day 14 without systemic adverse events. Although surgery for IMC is generally not an option, reduction in tumor size allowed surgery in two IMC patients. In peripheral blood, in situ eCPMV immunotherapy was associated with a significant decrease of Treg+/CD8+ ratio and changes in CD8+Granzyme B+ T cells, which behave as a lagging predictive biomarker. In the TME, higher neutrophilic infiltration and MPO expression, lower tumor Ki-67 PI, increase in CD3+ lymphocytes, decrease in FoxP3+/CD3+ ratio (p<0.04 for all comparisons), and no changes in CC-3+ immunostainings were observed in post-treatment tumor tissues when compared with pretreatment tumor samples. eCPMV-treated IMC patients had a statistically significant (p=0.033) improved overall survival than patients treated with medical therapy.Conclusions Neoadjuvant in situ eCPMV immunotherapy demonstrated anti-tumor efficacy and improved survival in IMC patients without systemic adverse effects. eCPMV-induced changes in immune cells point to neutrophils as a driver of immune response. Neoadjuvant in situ eCPMV immunotherapy could be a groundbreaking immunotherapy for canine IMC and a potential future immunotherapy for human IBC patients.https://jitc.bmj.com/content/10/3/e004044.full |
| spellingShingle | Daniel Alonso-Miguel Guillermo Valdivia Diego Guerrera Maria Dolores Perez-Alenza Stanislav Pantelyushin Angela Alonso-Diez Veronique Beiss Steven Fiering Nicole F Steinmetz Maria Suarez-Redondo Johannes vom Berg Laura Peña Hugo Arias-Pulido Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer Journal for ImmunoTherapy of Cancer |
| title | Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer |
| title_full | Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer |
| title_fullStr | Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer |
| title_full_unstemmed | Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer |
| title_short | Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer |
| title_sort | neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer |
| url | https://jitc.bmj.com/content/10/3/e004044.full |
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